Targeting the Protein LFA-1 Blocks Transplant Rejection

December 2010

Drs. Idelberto Badell (a PGY-3 general surgery resident), Mandy Ford, Allan Kirk, Chris Larsen and colleagues of the Transplant Immunology Lab and Yerkes Primate Research Center have developed a new immuosuppressive protocol that substantially prolongs the survival of transplanted pancreatic islets in nonhuman primates. As reported in "LFA-1–specific therapy prolongs allograft survival in rhesus macaques," The Journal of Clinical Investigation, Volume 120, Issue 12, the research team made considerable progress in their long-term focus on exploiting T cell costimulation blockade as an alternative strategy to avoiding the side effects of conventional immunosuppressive therapies. A rhesus macaque model of pancreatic islet cell transplantation was used to address the clear need for non-diabetes causing alternatives to currently available immunosuppressive regimens for islet transplant.

Donor specific T cells are keys mediators of transplant rejection, and lymphocyte function-associated antigen (LFA)-1 is an adhesion molecule that is expressed on T cells. Importantly, it is up-regulated on those T cells known as memory T cells that are thought to pose an immunological barrier to costimulation blockade-based therapies. Dr. Larsen's team was successful in applying the LFA-1–specific antibody TS-1/22 in combination with other drugs including the costimulation blockade drug belatacept to selectively inhibit LFA-1's ability to promote the donor specific T cell response.

"While costimulatory blockade has long proven capable of allograft protection in primates, including humans, it's not as effective by itself in the long-term as we'd like it to be," says Dr. Larsen. "In this study, adding LFA-1-specific induction to the process promoted islet allograft survival to a greater degree likely by targeting costimulation independent memory T cells, and impairing T cell trafficking to the transplanted islets. The anti–LFA-1–based regimens also did not impair the primates' health."

While Dr. Larsen and his study partners concluded that their results support the use of LFA-1–specific induction therapy to neutralize costimulation blockade–resistant populations of T cells, they emphasized that further evaluation of therapies targeting LFA-1 as a treatment for transplantation is necessary.